Project Summary/Abstract Social stress has adverse consequences for physical and mental health throughout life and its impact may be particularly relevant during adolescence as this is a time of substantial growth and reorganization of brain circuits. Social stress also has a differential impact in females compared to males though most research has focused on males. The proposed research uses the resident intruder model of social stress that we refined to understand how individuals cope during repeated social stress and how this determines individual consequences of repeated social stress for behaviors associated with depression and impaired cognitive function. Our research focuses on the locus coeruleus (LC) norepinephrine system, a major stress response system that mediates arousal and cognition in response to stress. The working hypothesis that frames this research is that individual differences in stress vulnerability result from differences in the circuitry that is engaged to regulate LC activity during stress. Specifically, excitatory regulation of the LC by corticotropin-releasing factor (CRF) and orexinergic afferents is hypothesized to underlie a passive coping style and vulnerability to stress-related disorders that are characterized by hyperarousal. In contrast, inhibitory enkephalin inputs to the LC are counterregulatory and are associated with a more active coping strategy and decreased vulnerability to those disorders. We hypothesize that LC-activating inputs and LC- inhibiting inputs are differentially altered in development and between sexes. This hypothesis is tested in 3 specific aims using technical approaches that include cellular measurements of receptor expression and trafficking, in vivo electrophysiology in behaving rats, chemogenetic manipulation of circuits using DREADDs and assessment of cognitive function and behavior. Aim 1 will identify stress-induced plasticity in circuits that regulate LC activity and how this is dependent on age and sex. Aim 2 will use DREADDs and neuropharmacological techniques to directly test the role of LC activity and its CRF, orexin A and enkephalin afferents in coping strategy in response to social stress. Aim 3 will test the role of the LC and its afferents on the pathological consequences of social defeat, including anhedonia, morphine conditioned place preference and cognitive function in the attention set-shifting test. Because coping strategy is an important determinant of stress resilience, the results of the proposed studies will significantly increase our understanding of how coping strategy can optimize activity of the LC-NE arousal system. The results will inform therapies designed to modify coping strategy in an effort to promote resilience and whether these therapies should be different depending on age and on sex.